tbuckley/cabot-search huggingface dataset:
EPEN-31. Developmental and Oncogenic Transcription Factor Circuits as Dependencies in Ependymoma
Authors: Stephen Mack
Journal: Neuro-Oncology (2022)

Abstract Brain tumors are the most common cause of cancer death in children. ZFTA-RELA gene fusion is one the most potent drivers of cancer and is sufficient to induce tumors when expressed during brain development. ZFTA-RELA (denoted ZRFUS) fusion is the most frequent events that occurs in an aggressive childhood brain tumor called ependymoma (&amp;gt; 70% of cases). ZFTA recruits RELA to novel DNA binding sites and is necessary to activate ependymoma oncogene transcription. There are currently no targetable treatments for ependymoma, thus studying the mechanisms that regulate ZRFUS oncogenic programs may yield opportunities to develop effective therapies. To study proteins that regulate gene expression programs in brain cancer, the Mack lab and others have comprehensively characterized the active chromatin landscapes of several adult and pediatric brain cancers. This genome-wide analysis has identified highly active TFs, termed core regulatory circuit (CRC) TFs that govern gene expression programs such as MYC, GLI2, SOX2, and OLIG1/2, previously described in brain tumors such as glioblastoma and medulloblastoma. Critically, a glial cell fate specification TF, SOX9, showed the highest levels of activity in ependymoma. A functional RNA interference screen of CRC TFs prioritized SOX9 as the top cancer dependency gene required for ZRFUS ependymoma cell proliferation. To study ZRFUS ependymoma, we developed one of the first genetic mouse models of the disease, and show in preliminary data, that SOX9 knockout abolishes tumor initiation. Surprisingly, SOX9 KO has no impact on tumor initiation in an aggressive glioma model, suggesting tumor-specific contributions of SOX9. This concept is supported by our data that shows SOX9 co-recruitment to a vast majority of ZRFUS binding sites in the genome. Our data supports that SOX9 regulates ZFTA-RELA target cistrome; presenting a potential pathway that may be explored for therapeutic benefit.
Evaluation of rechargeable InterStim™ micro system performance and safety: 3-month results from the OAB cohort of the ELITE study
Authors: D. Elterman, C. Goudelocke, K. Xavier, B. Pecha, K. Burgess, M-A. Perrouin-Verbe, R. Krlin, J. Michaels, S. Shah, B. Peyronnet, S. Zaslau, N. Grunow, K. Bittner, V. Nitti
Journal: European Urology (2022)
Inflammatory chemokines upregulated in the tumor microenvironment of prostate cancer patients experiencing relapse after radical prostatectomy
Authors: S. Krossa, M.K. Andersen, E. Midtbust, T. Viset, Ø. Størkersen, G.F. Giskeødegård, M.B. Rye, M-B. Tessem
Journal: European Urology (2022)
Knowledge matters: Chest radiology report generation with general and specific knowledge
Authors: Shuxin Yang, Xian Wu, Shen Ge, S. Kevin Zhou, Li Xiao
Journal: Medical Image Analysis (2022)

Automatic chest radiology report generation is critical in clinics which can relieve experienced radiologists from the heavy workload and remind inexperienced radiologists of misdiagnosis or missed diagnose. Existing approaches mainly formulate chest radiology report generation as an image captioning task and adopt the encoder-decoder framework. However, in the medical domain, such pure data-driven approaches suffer from the following problems: 1) visual and textual bias problem; 2) lack of expert knowledge. In this paper, we propose a knowledge-enhanced radiology report generation approach introduces two types of medical knowledge: 1) General knowledge, which is input independent and provides the broad knowledge for report generation; 2) Specific knowledge, which is input dependent and provides the fine-grained knowledge for chest X-ray report generation. To fully utilize both the general and specific knowledge, we also propose a knowledge-enhanced multi-head attention mechanism. By merging the visual features of the radiology image with general knowledge and specific knowledge, the proposed model can improve the quality of generated reports. The experimental results on the publicly available IU-Xray dataset show that the proposed knowledge-enhanced approach outperforms state-of-the-art methods in almost all metrics. And the results of MIMIC-CXR dataset show that the proposed knowledge-enhanced approach is on par with state-of-the-art methods. Ablation studies also demonstrate that both general and specific knowledge can help to improve the performance of chest radiology report generation.
Virtual classroom proficiency-based progression for robotic surgery training (VROBOT): A prospective, cross-over, effectiveness study
Authors: A. Asif, A. Nathan, S. Patel, M. Georgi, M.K. Hang, W. Mullins, M. Fricker, A. Ng, A. Ghosh, N. Francis, J. Collins, A. Sridhar
Journal: European Urology (2022)
MEDB-79. MYC-driven upregulation of the<i>de novo</i> serine and glycine pathway is a novel therapeutic target for Group 3 MYC-amplified Medulloblastoma
Authors: Magretta Adiamah, Janet C Lindsey, Florence Burté, Sarah Kohe, Alaide Morcavallo, Helen Blair, Rebecca M Hill, Mankaran Singh, Stephen Crosier, Tong Zhang, Oliver Maddocks, Andrew Peet, Louis Chesler, Ian Hickson, Ross Maxwell, Steven C Clifford
Journal: Neuro-Oncology (2022)

Abstract Despite advances in the molecular sub-classification and risk-stratification of medulloblastoma (MB), a subset of tumours remain refractory to current multimodal therapies. Group 3 (MBGroup3) patients represent around 25% of MBs, and amplification and elevated expression of MYC in this group correlates with dismal clinical outcomes. Since direct targeting of MYC remains elusive, understanding and exploiting metabolic dependencies in MYC-amplified MBGroup3 may reveal novel therapeutic opportunities. We engineered three independent regulable MYC-amplified MBGroup3 cell-based models, each harbouring doxycycline-inducible anti-MYC shRNAs (two independent species) or a non-silencing shRNA control. In all three models, MYC knockdown (KD) revealed persistent MYC-dependent cancer phenotypes, reduction in proliferation and cell cycle progression. We utilised 1H high-resolution magic angle spectroscopy (HRMAS) and stable isotope-resolved metabolomics to assess changes in intracellular metabolites and pathway dynamics when MYC expression was modulated. Profiling revealed consistent MYC-dependent changes in metabolite concentrations across models. Notably, glycine was consistently accumulated following MYC KD suggesting altered pathway dynamics. 13C-glucose tracing further revealed a reduction in glucose-derived serine and glycine (de novo synthesis) following MYC KD which was attributable to lower expression of PHGDH, the rate-limiting enzyme of this pathway. Furthermore, in human primary tumours, elevated expression of PHGDH was associated with MYC amplification and poorer survival outcomes. MYC expressing cells showed greater sensitivity to pharmacological inhibition of PHGDH compared to MYC KD (MBGroup3) and MBSHH subgroup cell lines in vitro. Critically, targeting PHGDH in vivo, using MYC-dependent xenografts and genetically engineered mouse models, consistently slowed tumour progression and increased survival. In summary, metabolic profiling has uncovered MYC-dependent metabolic alterations and revealed the de novo serine/glycine synthesis pathway as a novel and clinically relevant therapeutic target in MYC-amplified MBGroup3. Together, these findings reveal metabolic vulnerabilities of MYC-amplified MBGroup3 which represent novel therapeutic opportunities for this poor-prognosis disease group.
CoRInTH: A phase Ib/II trial of checkpoint inhibitor, pembrolizumab (PD-1 antibody [Ab]) plus standard intensity modulated chemoradiotherapy (IMCRT) in HPV-induced stage III squamous cell carcinoma (SCC) of the anus.
Authors: Marcia Hall, Richard Adams, Marianne Grønlie Guren, Margherita Carucci, Lisette Nixon, Catharine Porter, Neel Bhuva, Robert Glynne-Jones, Mark Harrison
Journal: Journal of Clinical Oncology (2022)

TPS3630 Background: SCC of anus (SCCA) are considered rare tumours, but the incidence is increasing. Only 65% patients with later stage T3/T4 +/-N1 SCCA remain disease free at 3 years (Gunderson 2013, James 2013). The cytotoxicity of IMCRT enhances tumour antigen presentation and promotes cytokine release as well as enhancing the MHC (Demaria 2004, Reits 2006). Immune therapy, against PD-1, have been approved for patients with SCC arising from other primary sites eg. head and neck, lung cancer. The addition of such checkpoint inhibitors might also result in improved PFS and OS for higher risk SCCA patients. Methods: A multicentre, single arm, open-label, non-randomised study to evaluate the safety and tolerability of different schedules of exposure to pembrolizumab (P) with standard IMCRT in 50 patients with locally advanced T3/4 anal cancer. The first cohort of 6 patients commenced standard IMCRT and received P 200mg every 21d beginning at Week 5 day 1 of the IMCRT schedule. If this is considered safe and tolerable with not more than 3/6 SAEs within first 6 weeks after completion IMCRT, a second cohort of 6 patients will be recruited where P is introduced on Week 1 Day 1 with standard IMCRT. Pembrolizumab monotherapy will be continued for a total of 6 months. Primary endpoint is safety and tolerability by assessing AEs and protocol adherence. Secondary endpoints include feasibility, clinical response assessment by RECIST (MRI) for ORR at 3, 6 and 12 months, imaging response assessments by TRG MRI using changes in Apparent Diffusion Coefficient (ADC) on diffusion weighted sequences and patient reported outcomes, using EORTC quality of life questionnaires. Patients are being asked to contribute to translational endpoints with the donation of tissue and blood samples. Eligible patients will have Stage IIIA/B (T3/4, any N, M0) SCCA, performance status 0 or 1 and be suitable for IMCRT. Patents with anal tumours of non-epithelial origin, metastatic disease or a diagnosis of immunodeficiency are excluded. Single phase IMRT with a simultaneous integrated boost to achieve 53.2Gy in 28 fractions over 5.5 weeks to PTV_A, according to the UK consensus is mandated. Concomitant chemotherapy can either be cisplatin 60mg/m2/ or mitomycin 12mg/m2 with either 5FU 1000mg/m2 or capecitabine 825mg/m2 at investigator discretion. The first cohort has completed recruitment with Safety Review Committee / IDMC review planned for April 2022. Patients will then be sought to start P on Week 1 Day 1 with IMCRT. Further safety review will be undertaken following the first 6 patients entered into the second cohort but recruitment will continue in an expansion phase to a maximum of 44 patients. Clinical trial information: NCT04046133.
Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: WJOG9717L Study
Authors: Hirotsugu Kenmotsu, Kazushige Wakuda, Keita Mori, Terufumi Kato, Shunichi Sugawara, Keisuke Kirita, Yasuto Yoneshima, Koichi Azuma, Kazumi Nishino, Shunsuke Teraoka, Takehito Shukuya, Ken Masuda, Hidetoshi Hayashi, Ryo Toyozawa, Satoru Miura, Daichi Fujimoto, Kazuhiko Nakagawa, Nobuyuki Yamamoto, Toshiaki Takahashi
Journal: Journal of Thoracic Oncology (2022)

IntroductionTo evaluate the efficacy and safety of osimertinib plus bevacizumab for previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations.MethodsWe conducted a randomized, open-label, phase 2 study at 21 institutions in Japan. Previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations received either osimertinib (80 mg, daily) plus bevacizumab (15 mg/kg, every 3 wk) or osimertinib monotherapy, and were stratified according to sex, stage, and EGFR mutation status. The primary end point was progression-free survival (PFS) in the intention-to-treat population, assessed by means of blinded, independent central radiologic review.ResultsBetween January 2018 and September 2018, a total of 122 patients were enrolled (osimertinib + bevacizumab arm, 61 patients; osimertinib monotherapy arm, 61 patients). At a median follow-up duration of 19.8 months, the median PFS was 22.1 months for osimertinib plus bevacizumab and 20.2 months for osimertinib monotherapy, with a hazard ratio of 0.862 (60% confidence interval: 0.700–1.060, 95% confidence interval: 0.531–1.397, one-sided stratified log-rank p = 0.213). Adverse events of grade 3 or worse were observed in 34 patients (56%) in the osimertinib plus bevacizumab arm and 29 (48%) in the osimertinib monotherapy arm. In addition, two (3%) and 11 patients (18%) experienced any grade pneumonitis, respectively, and grade 3 pneumonitis was observed in one patient (2%) in each arm.ConclusionsThis study failed to exhibit the efficacy of osimertinib plus bevacizumab for improving the PFS among patients with nonsquamous NSCLC harboring EGFR mutations as first-line treatment.
miR-6124: A potential new prognosis biomarker for lung squamous cell carcinoma through m5C regulating mechanism.
Authors: Qian Wang, Yuqing Zou, Shanshan Xiao, Tao Wang
Journal: Journal of Clinical Oncology (2022)

e20568 Background: RNA methylation is an important epigenetic modification that can act as tumor prognosis biomarkers, and which is regulated by methyltransferase, RNA binding protein, and demethylase. 5-Methylcytosine (m5C) is a well-known post-transcriptional modification that plays an important role in cell differentiation and apoptosis. Although gene mutations in those regulator genes are associated with various cancers, the m5C regulating mechanism and its roles in cancer prognosis largely remains unknown. This study aimed to find new microRNA biomarkers associated with prognosis of clinical outcomes through m5C regulating mechanism in lung squamous cell carcinoma (LUSC). Methods: The RNA-seq expression data of LUSC were collected from the The Cancer Genome Atlas (TCGA). In total, we obtained 501 LUSC tumor samples and 49 normal samples from 502 LUSC patients. We firstly identified differential expressed genes of the 13 previously reported m5C regulators between the tumor tissues and adjacent normal tissues. Then miRNAs were identified using Pearson correlation analysis between the microRNA expression and the differential expressed m5C regulator genes. Pathway enrichment analysis of the miRNAs was performed using clusterProfiler to examine their cancer development roles. Furthermore, cox regression analysis was used to evaluate the risk factor for overall survival. Targeted relationship between miRNA and genes were confirmed by miRTarBase. Results: Differential analysis revealed 4 significantly up-regulated (NOP2, NSUN2, DNMT3B and ALYREF) genes in tumor among 13 interested m5C regulators. Pearson correlation analysis identified 39 correlated miRNAs. After cox regression, we found out one micro-RNA miR-6124, which is highly correlated with DNMT3B gene and is significantly associated with worse overall survival (OS, p &lt; 0.01). We then identified the regulatory targets of miR-6124 using miRTarBase database. In total we identified 181 target genes. Among them, H3F3A which encode histone H3 synergistically work with DNMT3B gene as showed in the previous studies and promote DNA methylation of the oncogenes. Such preliminary results showed miR-6124 may be involved in cancer pathway regulating and was a potential prognosis biomarker candidate in LUSC. Conclusions: We identified a potential new prognosis biomarker in lung squamous cell carcinoma. The identified miR-6124 is involved in DNMT3B and m5C regulating mechanism. Further evidences are needed to study its’ role in clinical applications.
Health effects of exposure to residential air pollution in patients with pulmonary arterial hypertension: a cohort study in Belgium
Authors: Katleen Swinnen, Esmée Bijnens, Lidia Casas, Tim S. Nawrot, Marion Delcroix, Rozenn Quarck, Catharina Belge
Journal: European Respiratory Journal (2022)

<b>This cohort study showed that both exercise capacity and ESC/ERS risk assessment were associated with previous exposure to air pollutants in PAH patients. In contrast to previous data, no significant association with adverse outcomes was found.</b>https://bit.ly/3FwhJbz
A randomized trial of pegylated recombinant human granulocyte-colony stimulating factor to prevent febrile neutropenia in breast cancer after chemotherapy.
Authors: Lina Zhang, Yuntao Li, Zhonglin Fan, Meiqi Wang, Tianli Hui, Yanshou Zhang, Chunhui Gao, Jing Zhang, Guoshuan Zhang, Xiangshun Kong, Cuizhi Geng
Journal: Journal of Clinical Oncology (2022)

e12516 Background: The purpose of this study was to evaluate the incidence of febrile neutropenia (FN) in breast cancer patients with pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF) administration at 48 or 24 hours after chemotherapy for primary prevention. Methods: Patients with stage I-III invasive breast cancer who were scheduled to receive 4 cycles of adjuvant chemotherapy with EC regimen (epirubicin combined with cyclophosphamide) were eligible for this multicenter, open-label, randomized trial. Patients were randomized (1:1) to receive PEG-rhG-CSF (Jinyouli) 48 hours (48h group) or 24 hours (24h group) after the end of each cycle of chemotherapy. The primary endpoint was the incidence rate of FN. The secondary endpoints included the incidence rates of grade 3/4 neutropenia, chemotherapy dose reduction and chemotherapy delay due to neutropenia, antibiotic administration, the pain (bone, muscle, or joint), and the relative dose intensity (RDI) of the chemotherapy. Results: The preliminary results enrolled 197 patients including 96 in the 48h group and 101 in the 24h group. 78.1% of 48h group patients and 73.3% of 24h group patients completed four cycles of chemotherapy. The incidence rates of FN were 2.1% in the 48h group and 4.0% in the 24h group respectively. FN occurred in the first two cycles in the 48h group, while in the 24h group, it occurred only in the first cycles. The incidence rate of grade 3/4 neutropenia was 27.1% in the 48h group and 51.5% in the 24h group respectively. There was no delay in chemotherapy due to neutropenia in the two groups. The incidence rate of chemotherapy dose reduction due to neutropenia was 2.1% in the 48h group and 1.0% in the 24h group respectively. 2 (2.1%) patients in the 48h group and 4 (4.0%) patients in the 24h group received antibiotics. The mean RDI of each cycle of chemotherapy was 91.3% in the 48h group and 91.5% in the 24h group, respectively. The incidence rate of all grades pain (bone, muscle, or joint) was 25.0% in the 48h group, and 20.8% in the 24h group. With regard to 3 or higher grade pain, 1 (1.0%) patient in the 48h group experienced bone pain and 1 (1.0%) patient in the 24h group experienced muscle pain. Conclusions: Preliminary results suggest a similar effect of PEG-rhG-CSF administration at 48 or 24 hours after chemotherapy in primary prevention of FN in breast cancer patients receiving EC chemotherapy regimen. Recruitment is ongoing and updated data will be presented. Clinical trial information: ChiCTR1800019516. [Table: see text]
Salvage 177Lu-dotatate therapy in patients with progressive metastatic neuroendocrine tumors.
Authors: Hui Jing Hoe, David Wyld
Journal: Journal of Clinical Oncology (2022)

e16212 Background: 177 Lu-dotatate (LuPRRT) is effective in selected patients with metastatic neuroendocrine tumours (NETs). Most of these patients will subsequently have progressive disease with limited treatment options available. We analyzed the outcomes and toxicities of salvage LuPRRT in this study. Methods: This is a retrospective cohort study. Patients who had salvage LuPRRT at Royal Brisbane and Women’s Hospital (RBWH) from November 2016 to January 2021 were identified and included in this study. We manually reviewed the hospital electronic medical records and radiology databases to review patient characteristics, outcomes, and toxicities from salvage LuPRRT. Results: Of the 37 patients included, 37.8% (14/37) had small bowel primary, 27.0% (10/37) had pancreatic primary and 10.8% (4/37) had pulmonary primary. 83.8% (31/37) received 4 cycles of initial LuPRRT (I-PRRT) with a median dose of 32.0 GBq. The median duration of response to I-PRRT was 31 months. These patients had salvage LuPRRT (R-PRRT) on progression with 83.8% (31/37) received 2 cycles with a median cumulative 177 LuTate dose of 48.0 GBq. Partial response, stable disease and progressive disease were observed in 10.8% (4/37), 40.5% (15/37) and 27.0% (10/37) of patients respectively. Median duration of response with R-PRRT was 8 months. 2.7% (1/37) developed Grade 3 anaemia and 2.7% (1/37) developed Grade 3 thrombocytopenia with R-PRRT. 8.1% (3/37) developed nephrotoxicity Grade 1 nephrotoxicity. 21.6% (8/37) of patients had re-retreatment with further LuPRRT (RR-PRRT) on progression. The median retreatment cycles were 2 and the median cumulative 177 LuTate dose received was 58.8 GBq. Partial response, stable disease and progressive disease were seen in 25% (2/8), 12.5% (1/8) and 62.5% (5/8) of patients respectively. Median duration of response with RR-PRRT was 4 months. There were no reported Grade 3 haematologic toxicities with RR-PRRT. 1 patient developed Grade 1 nephrotoxicity with RR-PRRT. At time of data analysis in April 2021, 27% (10/37) had ongoing response while 73% (27/37) had progressed. Conclusions: Salvage LuPRRT is an effective and safe treatment option for selected patients with progressive metastatic NETs.
Impact of cachexia on the efficacy of first-line immunotherapy in extensive-stage small-cell lung cancer patients.
Authors: Xinyu Fan, Butuo Li, Linlin Wang
Journal: Journal of Clinical Oncology (2022)

e20620 Background: This study was to investigate the association between cachexia and prognosis in extensive-stage small-cell lung cancer(ES-SCLC) patients who received first-line immunotherapy. And the prognostic values of some systematic inflammatory and nutritional indexes were also evaluated. Methods: Data of 123 ES-SCLC patients receiving immunotherapy as first-line treatment in one single center from June 2019 to February 2021 were analyzed. Development of cachexia after the initiation of immunotherapy was defined as patients with more than 5% weight loss over past 6 months, or more than 2% weight loss with body mass index (BMI) less than 20 kg/m 2 . Endpoints included response rate, progression-free survival (PFS) and overall survival (OS). Univariate and multivariate survival analysis were performed to identify the factors correlated with PFS and OS. Results: At evaluation after 6 months of initial treatment, cachexia was presented in 51 patients(41.5%). The treatment response and survival of patients with cachexia were worse than those without. The overall median overall survival (OS) was 14.4 months (95% CI 13.3–15.6). The overall median progression-free survival (PFS) was 8.1 months (95% CI 7.0–9.2). The median PFS was significantly longer in patients without bone metastases at diagnosis(HR = 2.362,95%CI:1.452-3.842;p = 0.001), without cachexia(HR = 1.802,95% CI: 1.121-2.895; p = 0.015), and with lower change of total protein(HR = 1.799,95% CI: 1.084–2.984; p = 0.023). The median OS was significantly shorter in patients with poor ECOG PS (HR = 1.904, 95% CI: 1.017-3.564; p = 0.044), higher baseline SII (HR = 2.135,95% CI: 1.117–4.080; p = 0.022), with cachexia(HR = 2.020,95% CI: 1.075-3.795; p = 0.029), advance M stage(HR = 3.111,95% CI:1.545–6.262; p = 0.001) and higher post-treatment SIRI (HR = 2.135,95% CI: 1.281–4.697; p = 0.007). Conclusions: ES-SCLC patients who develop cachexia after first-line immunotherapy have a poor prognosis. our study also confirms that baseline SII and SIRI at 6 weeks after treatment appears to be promising predictors for OS of ES-SCLC who treated with first-line immunotherapy.